1. Field of the Invention
The present invention is directed to the discovery that a certain family of interferons, the alpha-type interferons, demonstrate a previously unrecognized utility in the treatment of essential (hemorrhagic) thrombocythemia. The treatment, comprising administration of effective amounts of alpha-type interferons, substantially reduces the risk of thrombosis in patients suffering from the disease.
2. Brief Description of the Background Art
Interferon is a potent antiviral glycoprotein released by animal cells following viral infection and also after treatment of such cells with certain nonviral inducers. This constitutes one of the major defense mechanisms against viral infections in mammals, including humans. In addition to its antiviral function, interferon has been found to have immunoregulatory activities, to affect various cellular functions including cell division, and to have value as an anti-cancer drug.
Much research and developmental effort has been applied to the large scale production of human interferon. Interferons are used to treat virus diseases and also to treat tumors of viral and/or non-viral origin (see, for example, Powledge, Bio/Technology, "Interferon On Trial," pp. 215-222, March 1983).
Human interferons (HuIFN) have been classified into three groups: alpha-interferon (HuIFN-alpha), beta-interferon (HuIFN-beta) and gamma-interferon (HuIFN-gamma). HuIFN-alpha, also known as leukocyte interferon, is produced in human leukocyte cells and together with minor amounts of HuIFN-beta, also called fibroblast interferon, in lymphoblastoid cells. HuIFN-gamma is produced in cultures of lymphocytes, particularly in cultures enriched for T-cells.
Only one type each of HuIFN-beta and HuIFN-gamma has been found in the human organism (Ohno, S. et al., Proc. Natl. Acad. Sci., 76: 5305-5309 (1981); Gray et al., Nature, 295: 503-508 (1982); Taya et al., EMBO Journal, 1/8: 953-958 (1982)). On the other hand, various sub-types of HuIFN-alpha are known from the literature (Phil. Trans. R. Soc., London, 299: 7-28 (1982); and British Patent Application No. 2,037,296A). The various forms of HuIFN-alpha, hereinafter alpha-type interferons, appear to differ from each other structurally and physiologically. However, they all appear to be about 166 amino acids long with the mature interferons differing from one another by a divergence of up to about 25% of the amino acid sequences. The interferons currently used therapeutically in human medicine are obtained from human leukocytes, from reproducible human fibroblasts, and human lymphoblastoid cell cultures and from microorganisms. The human genes coding for interferon are incorporated in various microorganisms, including E. coli. The production of alpha-type interferon using recombinant DNA technology is described in European Patent Application No. 0 032 134, published Aug. 15, 1984, and European Patent Application No. 0 043 980, published Jan. 20, 1982, both incorporated by reference herein.
Thrombocytosis is a term used to describe a temporary elevation of platelet count above 400.times.10.sup.3 /ul which may occur after severe hemorrhage, surgery, or splenectomy. The condition exists as well in cases of iron deficiency. Thrombocytosis may also occur in chronic inflammatory disorders and following recovery from acute infection. Malignant diseases such as carcinoma and Hodgkin's disease may also be associated with thrombocytosis. See Harrison's Principles of Internal Medicine, Tenth Edition, McGraw-Hill, Inc., p. 1898 (1983).
Thrombocythemia refers to a sustained elevation of platelet count, usually above about 800.times.10.sup.3 /ul. This condition, generally considered to be a myeloproliferative disorder, usually manifests itself with the spleen sufficiently enlarged to be detected by abdominal palpation. Thrombocythemia may occur as a part of polycythemia vera, chronic myelogenous leukemia, or myelosclerosis. It may also occur alone, in which case it is termed essential (hemorrhagic) thrombocythemia. Patients with essential thrmobocythemia frequently manifest spontaneous bleeding as well as venous and arterial thrombosis. Platelet function studies such as aggregation and platelet factor III activity are often abnormal. See Harrison's, supra, p. 1898.
Prior art treatment for essential thrombocythemia involves therapy to decrease the autonomous growth of megakaryocyte and the resulting excessive platelet production. Suitable reagents for this type of therapy includes .sup.32 P, busulfan, or another alkylating agent. See Harrison's, supra, p. 1898. Where thrombosis develops, heparin therapy is required. Aspirin and dipyridamole have been successfully used in peventing thrombosis.
Talpaz et al., Ann. Intern. Med., 99: 789-792 (1983), has described the use of HuIFN-alpha prepared according to Cantrell et al. (J. Gen. Virol., 39: 541-543 (1973)) for adjunct therapy in the treatment of thrombocytosis in patients with chronic myelogenic leukemia. The patients were simultaneously treated by chemotherapy with cytostatics, e.g. with cyclophosphamide, cytarabine, vincristine, hydroxyurea, 6-mercapto-purine, busulfan and mixtures thereof. However, this methodology resulted in serious side effects such as fever, weight loss, neuromuscular pains, and the like. Similar deleterious side effects are reported at J. Gen. Virol., 63: 354-363 (1982) and N. Eng. J. Med., 308: 553-558 (1983).
Further, during treatment with cytostatics or mixtures thereof, the number of white blood corpuscles and blood platelets (thrombocytes) is generally always reduced. Accordingly, the dosage of cytostatics used must be selected so that the resulting side effects, e.g., the lowering of resistance to infections and anemia, remain tolerable in relation to the objective of the therapy.
However, in spite of the many advances reported in the use of HuINF-alpha for the treatment of a variety of diseases of tumor and viral origin, and even in the face of the Talpaz et al. (supra) disclosure relaing to the treatment of chronic myelogenic leukemia and the thrombocytosis resulting therefrom by a combination of HuIFN-alpha and various cytostatics, a need has continued to exist for a safe and effective treatment for thrombocythemia which avoids the undesirable side effects of chemotherapy with cytostatics.